82

REPORTS ALERTS, NOTICES, AND CASE REPORTS~~~~

serum precedes the symptomatic illness. 13.14 In summary, this case illustrates well the clinical-virologic correlates of acute delta virus infection in a human carrier of hepatitis B. We are intrigued by the ability of the delta hepatitis virus to establish an infection and replicate during treatment with a nucleoside analogue, as well as the ability of this patient with a simultaneous HIV infection to clear all markers of active HBV and HDV hepatitis. REFERENCES

1. Rizzetto M, Canese MG, Arico S, et al: Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 1977; 18:997-1003 2. Rizzetto M, Canese MG, Gerin JL, et al: Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. J Infect Dis 1980; 141:590-602 3. Smedile A, Farci P, Verme G, et al: Influence of delta infection on severity of hepatitis B. Lancet 1982; 2:945-947 4. Rizzetto M, Verme G, Pecchia S, et al: Chronic hepatitis in carriers of hepatitis B surface antigen, with intrahepatic expression of the delta antigen: An active and progressive disease unresponsive to immunosuppressive treatment. Ann Intern Med 1983; 98:437-441 5. De Cock KM, Govindarajan S, Chin KP, et al: Delta hepatitis in the Los Angeles area: A report of 126 cases. Ann Intern Med 1986; 105:108-114 6. Bonino F, Smedile A: Delta agent (type D) hepatitis. Semin Liver Dis 1986; 6:28-33 7. Caredda F, Rossi E, d'Arminio Monforte A, et al: Hepatitis B virus-associated coinfection and superinfection with delta agent: Indistinguishable disease with different outcome. J Infect Dis 1985; 151:925-928 8. Hadler SC, De Monzon M, Ponzetto A, et al: Delta virus infection and severe hepatitis: An epidemic in the Yucpa Indians of Venezuela. Ann Intern Med 1984; 100:339-344 9. Ponzetto A, Cote PJ, Popper H, et al: Transmission of the hepatitis B virusassociated delta agent to the eastern woodchuck. Proc Natl Acad Sci 1984; 81:2208-2212

Disseminated Pneumocystis carinii in a Patient Receiving Aerosolized Pentamidine Prophylaxis STEPHEN M. BERMAN, MD, PhD BEENA SHAH, MD FREDERIC A. WYLE, MD MARIA DACOSTA-IYER, MD D. MICHAEL McRAE, MD Long Beach, California

Pneumocystis carinii is an organism with an almost exclusive predilection for infecting the lungs of immunocompromised patients. It is the most commonly diagnosed opportunistic infection in patients with the acquired immunodeficiency syndrome (AIDS), occurring in from 60% to 70% of these patients. The mortality rate can be as high as 50%.1 Preventing P carinii pneumonia is important because of the rapid rise in mortality with each successive episode of pneumonia. To that end, the combination of trimethoprim and sulfamethoxazole has been used effectively as an oral prophylactic agent in patients infected with the human immunodeficiency virus (HIV) who also have Kaposi's sarcoma.2 It is not clear whether intravenous pentamidine is suitable for prophylaxis. When given in an aerosolized form, however, pentamidine has been shown to be effective in the treatment of P carinii pneumonia3.4 and in

(Berman SM, Shah B, Wyle FA, et al: Disseminated Pneumocystis carinii in a patient receiving aerosolized pentamidine prophylaxis. West J Med 1990 Jul; 153:82-86) From the Infectious Diseases Section, Medical Service (Drs Berman, Shah, and Wyle), and Laboratory Service (Drs Dacosta-Iyer and McRae), Veterans Administration Medical Center, Long Beach, California. Reprint requests to Stephen M. Berman, MD, PhD, VA Medical Center, Infectious Diseases Section, Medical Service, 5901 E Seventh St, Long Beach, CA 90822.

10. Robinson WS: DNA and DNA polymerase in the core of the Dane particle of hepatitis B. Am J Med Sci 1975; 270:151-159 11. Garcia G, Smith CI, Weissberg JI, et al: Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leukocyte interferon in the treatment of chronic hepatitis B: A randomized, double-blind, placebocontrolled trial. Ann Intern Med 1987; 107:278-285 12. Merigan TC, Gregory PF, Petralli JK: Physical properties of human interferon prepared in vitro and in vivo. Virology 1966; 29:515-522 13. Smedile A, Rizzetto M, Denniston K, et al: Type D hepatitis: The clinical significance of hepatitis D virus RNA in serum as detected by a hybridizationbased assay. Hepatology 1986; 6:1297-1302 14. Bergmann KF, Gerin JL: Antigens of hepatitis delta virus in the liver and serum of humans and animals. J Infect Dis 1986; 154:702-706 15. Leevy CM (Ed): Diseases of the Liver and Biliary Tract With Standardization of Nomenclature, Diagnostic Criteria and Diagnostic Methodology. New York, S. Karger, 1976 16. Govindarajan S, De Cock KM, Redeker AG: Natural course of delta superinfection in chronic hepatitis B virus-infected patients: Histopathologic study with multiple liver biopsies. Hepatology 1986; 6:640-644 17. Dragosics B, Ferenci P, Hitchman E, et al: Long-term follow-up study of asymptomatic HBsAg-positive voluntary blood donors in Austria: A clinical and histologic evaluation of 242 cases. Hepatology 1987; 7:302-306 18. Davis GL, Hoofnagle JH, Waggoner JG: Acute type A hepatitis during chronic hepatitis B virus infection: Association of depressed hepatitis B virus replication with appearance of endogenous alpha interferon. J Med Virol 1984; 14: 141-147 19. Novick DM, Lok ASF, Thomas HC: Diminished responsiveness of homosexual men to antiviral therapy for HBsAg-positive chronic liver disease. J Hepatol 1984; 1:29-35 20. Krogsgaard K, Lindhardt BO, Nielson JO, et al: The influence of HTLV-III infection on the natural history of hepatitis B virus infection in male homosexual HBsAg carriers. Hepatology 1987; 7:37-41 21. Chin KP, Govindarajan S, Redeker AG: Permanent HBsAg clearance in chronic hepatitis B viral infection following acute delta superinfection. Dig Dis Sci 1988; 33:851-856 22. Aragona M, Macagno S, Caredda F, et al: Serological response to the hepatitis delta virus in hepatitis D. Lancet 1987; 1:478-480

preliminary studies was shown to be an effective prophylactic agent in preventing pneumonia caused by P carinii.5 6 Recently the Food and Drug Administration approved the use of aerosolized pentamidine isethionate for prophylaxis against P carinii pneumonia in patients infected with HIV. While this method of administration achieves high levels of the drug in the lungs, it does not produce substantial levels in the serum and, thus, is likely to produce low levels in extrapulmonary tissues.7 We report a case of a patient with AIDS in whom an unusual syndrome of hypoalbuminemia developed while he was receiving aerosolized pentamidine prophylaxis and who, on autopsy, was found to have widely disseminated P carinii that was thought to contribute substantially to his death.

Report of a Case The patient, a 45-year-old homosexual man, first tested positive for HIV in October 1986. He was admitted to the Long Beach Veterans Administration Medical Center in March 1987 with Pneumocystis carinii pneumonia and was given a 21-day course of intravenous pentamidine. Zidovudine therapy was started in May 1987. In November 1987 he had a second bronchoscopically confirmed episode of P carinii pneumonia. Therapy consisted of aerosolized pentamidine isethionate at 600 mg per day (diabetes mellitus had developed after the administration of intravenous pentamidine). Over the next 12 months, he had two more episodes of P carinii pneumonia, both of which responded to the use of aerosolized pentamidine. The last episode, in November 1988, occurred despite the institution of prophylactic aerosolized pentamidine at 300 mg per month four months previously. At that time, however, he was noted to have a severe retinitis thought to be consistent with cytomegalovirus infection, and he was started on a regimen of ganciclovir (9-[1,3-dihydroxy-2-propoxymethyl]-guanine). At the time that therapy with ganciclovir was instituted, the patient was noted to have peripheral edema, and liver

THE WESTERN JOURNAL OF MEDICINE THE WESTERN

JOURNAL OF

MEDICINE

JULY 1990

*

JULY

1990

,

*

153 153

e *

83

1 1

ABBREVIATIONS USED IN TEXT AIDS = acquired immunodeficiency syndrome ALT = alanine aminotransferase AST = aspartate aminotransferase HIV = human immunodeficiency virus LDH = lactate dehydrogenase TMP-SMX = trimethoprim-sulfamethoxazole

function tests showed an alkaline phosphatase level of 370 units per liter, a lactate dehydrogenase level (LDH) of 737 units per liter, aspartate aminotransferase (AST; formerly SGOT) 239 units per liter, alanine aminotransferase (ALT; formerly SGPT) 219 units per liter, and a profound hypoalbuminemia with a serum albumin level of 11 grams per liter. The results of a physical examination and chest x-ray film were consistent with bilateral pleural effusions, mild congestive heart failure, and ascites. A nuclear liver-spleen scan revealed generalized hepatocellular dysfunction and multiple areas of reduced translucence in the spleen thought to be consistent with either abscess, tumor, or cystic disease. An abdominal ultrasonogram was interpreted as showing a diffuse process involving the liver, spleen, and kidneys. A computed tomographic scan showed scattered low-density lesions in the liver, spleen, and kidneys along with calcifications within the kidneys. His shortness of breath abated after diuresis, and he had no respiratory complaints. On December 12, 1988, his liver function tests showed a progressive deterioration with a serum albumin of 8 grams per liter, alkaline phosphatase 1,130 units per liter, LDH 820 units per liter, AST 235 units per liter, ALT 161 units per liter, and y-glutamyl transferase 228 units per liter. A prothrombin time was 14.4 seconds, and the partial thromboplastin time was 38.8 seconds. A liver biopsy specimen revealed numerous patchy areas of necrosis with a "foamy" infiltrate on hematoxylin and eosin stain but without an inflammatory infiltrate around these areas of necrosis. No granulomas were seen. A Gomori methenamine-silver stain showed no organisms; in particular, no cysts consistent with P carinii could be found. An acid-fast stain was negative, and cultures for bacteria, acidfast bacilli, and viruses were all negative. Serologic tests for hepatitis A and B were also negative. A 24-hour urine collection showed less than 0.005 grams of protein. His serum albumin value continued to decrease, eventually reaching 2 grams per liter.

During the hospital stay he received several transfusions of salt-poor albumin. Each transfusion resulted in a rise in his serum albumin level, but the increase was transient, and his albumin would quickly fall back to 2 grams per liter. The patient's condition deteriorated, and he died on January 15, 1989. After his death, a culture of his peritoneal fluid from December 30, 1988, grew Mycobacterium avium-intracellulore. At autopsy, the lungs displayed firm, pale areas. The lymph nodes were enlarged and dark, and the spleen was enlarged with 2- to 4-mm miliary lesions that were noted also in the liver and both kidneys. In the spleen, lymph nodes, bone marrow, heart, stomach, liver, pancreas, adrenal glands, and kidneys, there were foamy or vacuolated necrotic areas containing fibrin and sometimes visible calcium (Figure 1). These foamy areas resembled those noted in the lungs that were shown to contain P carinii. This was confirmed by the finding of a small number of typical Pneumocystis organisms in most of the suspect (foamy-appearing) extrapulmonary sites (Figures 2 and 3). In addition, a moderate number of acid-fast bacilli were seen in the

It

i-e'; * v .* *

J; g s ^ ..

s

.~ ~ ~

..

...

;i

tf

,

&

,

.i

F4

'X t %. > ..

Figure 2.-A specimen of liver shows a "foamy" area with a cyst form of Pneumocystis carinii in the center of the area (arrow) (Gomori methenaminesilver stain, original magnification x 1,000). AA,

r'

ip-

.

I

lk*W.

04""':1

4e

'I.,

....

-

'. Ik

I

V.4a .

P-VP~a

&W4 e.*

#0V~~~~~~~~~~~-~

..-

.ft-

"b WAIPIQ %V -.

'.P irv

I41 A.-~~~~~~~~~~~~~~~~~~.-

IL~~~~~~~s ep ~

~

~

t'P."

I

ax

-,,

*

~ "'

t-

A,

Figure 1.-At autopsy, a specimen of liver shows (hematoxylin and eosin stain, original magnification

a x

miliary "foamy" 200).

area

.*P

.g s.

.t

-

Figure 3.-A specimen of adrenal gland shows a cluster of Pneumocystis corinii in the central foamy area (curved arrows). Macrophages filled with acid-fast bacilli (straight arrows) are seen in the lower portion (Gomori methenamine-silver stain, original magnification x 1,000).

84

ALERTS, NOTICES, AND CASE REPORTS

macrophages of the lymph nodes, spleen, liver, and adrenal glands. Cultures of specimens from the liver and spleen grew M avium-intracellulare. No evidence of necrosis or inflammation was seen around these organisms or within or near the foamy-appearing areas that contained the Pneumocystis organisms. Discussion

Pneumocystis carinii is a well-known cause of pneumonitis in immunocompromised patients. What is rarely recognized is the fact that P carinii can disseminate and infect extrapulmonary sites. Before the discovery of AIDS, there were several widely scattered reports of extrapulmonary pneumocystosis.8-18 With the advent of AIDS, several more cases of extrapulmonary pneumocystosis have been reported."9-35 We found 32 reported cases of disseminated P carinii in the English-language literature (Table 1). In all 14

of the non-AIDS cases in which P carinii was found in extrapulmonary sites the patients had some form of immunocompromise, ranging from hypogammaglobulinemia or agammaglobulinemia to cancer chemotherapy to immunosuppressive therapy after a renal transplant. All of these cases ended in the death of the patient, and in only four was the diagnosis made antemortem. One patient received primaquine phosphate, an antimalarial drug with some activity against P carinii. No other patient received therapy that would be considered even partially effective against P carinii. In addition, P carinii was found in the lungs of all 14 of these patients at autopsy. One case, patient 3 (Table 1), was strikingly similar to that of our patient. That patient also had P carinii in his liver, and he, too, presented with pronounced edema, ascites, and a severe hypoalbuminemia that defied diagnosis until his death.

TABLE 1.-Pneumocystis carinii Infection With Extrapulmonary Involvement Patient

Sites of Infection With P carinii

1.. Lungs, hilar lymph node 2.. Lymph nodes (tracheal) 3.. Lungs, liver, spleen, lymph nodes, bone marrow 4.. Lung, lymph nodes, spleen 5.. Lungs, lymph nodes 6.. Lungs, lymph nodes 7.. Lungs, lymph nodes, liver, colon, pericardium, pancreas, bone marrow 8.. Lungs, lymph nodes, thymus 9.. Lungs, lymph nodes, spleen

Immunosuppressive Condition

Anti-P carinii Therapy

Outcome

Reference

None None Primaquine phosphate

Death Death Death

(idiopathic hypoproteinemia) Hypogammaglobulinemia Hypogammaglobulinemia Leukemia with chemotherapy Renal transplant;

Anderson and Barrie, 19608 Livingstone, 19649 Jarnum et al, 1968 10

None None None None

Death Death Death Death

Barnett et al, 19691 Barnett et al, 1969" Barnett et al, 19691" Awen and Baltzan, 197112

steroid therapy Agammaglobulinemia Hypogammaglobulinemia

None None

Death Death

Thymic alymphoplasia

None

Death

Burke and Good, 197313 LeGolvan and Heidelberger, 197314 Rahimi, 1974's

Hypogammaglobulinemia

None

Death

Henderson et al, 197416

Leukemia Hodgkin's disease Lymphoma with chemotherapy AIDS AIDS

None None None TMP-SMX None

Death Death Death Recovered Death

Price and Hughes, 197417 Rossi et al, 198518 Rossi et al, 198518 Carter et al, 198819 Unger et al, 198820

Undetermined Agammaglobulinemia

Hypogammaglobulinemia

10. . Lungs, heart, liver, stomach, small intestine, spleen, kidneys, bone marrow 11.. Lungs, blood vessel walls, lymph node 12 Lungs, spleen 13 Lungs, bone marrow 14 Lungs, bone marrow 15 Small intestine, lymph node 16 . . Lungs, lymph nodes, adrenal glands, bone marrow 17 Widely disseminated, including the eyes 18 Widely disseminated

AIDS

TMP-SMX

Death

Macher et al, 198721

AIDS

Death

Grimes et al, 198722

19 . Ear (cutaneous) 20 Ear 21 Lungs, eyes

AIDS AIDS AIDS

Recovered Recovered

Coulman et al, 198723 Schinella et al, 198724

22.. Spleen 23 Lunas, lymph nodes

AIDS AIDS

Death Recovered Death

Kwok et al, 198225 Pilon et al, 198726 Raviglione et al, 198927

Death Recovered

Raviglione et al, 198927 Richie et al, 198928

Death Recovered

Hardy et al, 198929 Sparling et al, 198930

Recovered

Poblete et al, 198931

Recovered

Piot et al, 198932

Death

Hagopian and Huseby, 198933

Death

Davey et al, 198934

Death

Afessa et al, 198835

24 25

Lungs, stomach, duodenum Liver, ?eyes

AIDS AIDS

26 27

Liver, spleen, kidneys, lymph node Lymph node, liver

AIDS AIDS

28

Liver

AIDS

29

Spleen

AIDS

30

Liver, ?eyes

AIDS

31

Widely disseminated, including the lungs Lungs, liver, spleen, lymph nodes

AIDS

Intravenous (IV) pentamidine TMP-SMX TMP-SMX TMP-SMX; IV pentamidine IV pentamidine Aerosolized pentamidine; IV pentamidine Aerosolized pentamidine Aerosolized pentamidine, TMP-SMX Aerosolized pentamidine Aerosolized pentamidine; trimethoprim and dapsone Aerosolized pentamidine, IV pentamidine Aerosolized pentamidine, IV pentamidine Aerosolized pentamidine, IV pentamidine Aerosolized pentamidine

AIDS

None

32

AIDS=acquired immunodeficiency syndrome, TMP-SMX=trimethoprim and sulfamethoxazole

THE WESTERN JOURNAL OF MEDICINE

* JULY 1990 *

153

*

1

Since 1982 there have been scattered reports of extrapulmonary pneumocystosis in patients with AIDS.'9-35

These

cases are different from the previously reported 14 In 14 of 18 cases, the diagnosis of P carinii infection was made antemortem. In 11 cases, the patient had at least one episode of pneumonia before the documentation of extrapulmonary Pneumocystis organisms. Also, many of the patients with AIDS recovered from their P carinii infection. Of significance are the recent reports of nine cases similar to this one, where the patient was receiving aerosolized pentamidine as prophylaxis against P carinii pneumonia."-" These cases are the only ones where the patients had received any prophylaxis against this disease. Preventing P carinii pneumonia is important because the mortality increases with each episode. Several studies have shown that it can be effectively prevented in immunosuppressed patients without AIDS.36-38 In particular, a double-blind study showed trimethoprim-sulfamethoxazole (TMP-SMX) to be highly effective as a prophylactic agent in patients with cancer. Recently, TMP-SMX has been shown to be efficacious in preventing P carinii pneumonia in patients with AIDS.2 The study patients were all HIV-positive, had Kaposi's sarcoma, and had no prior history of opportunistic infections. Over a 24-month period, P carinii pneumonia developed in none of 30 patients receiving TMP-SMX, but it did develop in 16 of 30 patients receiving no suppressive therapy. This was a study on primary prophylaxis. Because of this study and much anecdotal evidence, many physicians have advocated prophylaxis against P carinii pneumonia for at least all patients who are HIV-positive and who have had at least one episode of the pneumonia. Many physicians feel that all patients infected with HIV should receive prophylaxis, regardless of whether they have had P carinii pneumonia; recent data support this position

cases.

for patients with CD4 counts of less than 2

x

106 cells per

liter (< 200 per l).39 Although TMP-SMX was efficacious in the one group of patients studied, its use has not been proved effective yet in other groups of patients with AIDS, specifically in patients who have already had pneumonia. In addition, TMP-SMX is fairly toxic, with a substantial number of patients having bone marrow suppression (especially leukopenia), severe rashes, or both.40 The marrow toxicity may be magnified in patients who are receiving other marrow suppressive drugs such as zidovudine or ganciclovir. Because of those factors, researchers have been trying to develop prophylactic regimens that are less toxic but effective. Pentamidine isethionate has been shown to be as effective, when given parenterally, as TMP-SMX for the treatment of P carinii pneumonia.41 In addition, pentamidine has also been shown to be effective in the treatment of mild cases of the disease when it is given in an aerosolized form.34 Since that finding, studies were done on the efficacy of aerosolized pentamidine as a prophylactic agent against P carinii pneumonia. Preliminary data indicate that it is effective when given once each month.5 Because of this and the widespread use of similar regimens in the community, the Food and Drug Administration recently approved the use of aerosolized pentamidine as prophylaxis against P carinii pneumonia. Given the relative lack of toxicity of aerosolized pentamidine treatments (bronchospasm being the major adverse effect) and the ease of its administration, this form of prophylaxis will likely become the standard of care in the community at large, especially if its effectiveness as

prophylaxis

against P carinii pneumonia is reconfirmed

,in further trials. Regardless of when it is acquired or how it is spread, it should be emphasized that P carinii causes clinically appar-

85

ent and significant disease almost exclusively in the lungs; extrapulmonary organs rarely show clinical involvement. This predilection may be exaggerated in HIV-positive patients by our therapeutic interventions, as these patients are often treated empirically for P carinii pneumonia with the parenteral administration of TMP-SMX or pentamidine when pulmonary symptoms develop. In doing this we are also treating, or at least suppressing, any P carinii that may be located in extrapulmonic tissues. Administering aerosolized pentamidine appears to be a relatively nontoxic method of providing prophylaxis against P carinii pneumonia in HIV-positive patients. Because of its pharmacokinetics, however, it does not appear to achieve significant levels in tissues outside of the lungs and thus provides no prophylaxis against extrapulmonary P carinii.7 Trimethoprim-sulfamethoxazole prophylaxis potentially provides both local and systemic protection against P carinii, but it is a more toxic agent than aerosolized pentamidine. Our patient had an extremely unusual presentation, with a profound hypoalbuminemia. On autopsy, organisms consistent with both P carinii and M avium-intracellulare were found in all tissues examined, including the liver. It is probable that P carinii was responsible for the patient's presentation owing to the following: * The areas of necrosis and obvious pathology in the liver seemed to correspond with the areas in which P carinii was found and not with the areas in which the M aviumintracellulare was seen. * Infection with M avium-intracellulare is commonly found and reported in HIV-positive patients. An extensive literature review has not elicited any reported cases of M avium-intracellulare infection that resemble this case. * Disseminated P carinii infection is a rare event, and there are three cases reported previously that are almost identical in appearance to this case.10.31.33 Clinicians should be aware of the possibility of disseminated P carinii in patients who receive aerosolized pentamidine for prophylaxis. This therapy appears to be effective in suppressing the formation of pneumonia due to this pathogen. With effective pulmonary prophylaxis helping to prolong life, however, we may be allowing those organisms outside of the lungs time to flourish and thus to cause clinical disease that was previously not seen. In such patients who present with unusual symptoms, particularly those with liver function abnormalities and a decreased serum albumin level, disseminated P carinii should be considered in the differential diagnosis. This may be an indication for aggressive workup to look for disseminated P carinii or might warrant a switch to empiric parenteral therapy that is also effective against P carinii. REFERENCES 1. Armstrong D, Gold JWM, Dryjanski J, et al: Treatment of infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1985;

103:738-743 2. Fischl MA, Dickinson GM, La Voie L: Safety and efficacy of sulfamethoxazole and trimethoprim chemoprophylaxis for Pneumocystis carinii pneumonia in AIDS. JAMA 1988; 259:1185-1189 3. Montgomery AB, Debs RJ, Luce JM, et al: Aerosolised pentamidine as sole therapy for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet 1987; 2:480-483 4. Conte JE, Hollander H, Golden JA: Inhaled or reduced-dose intravenous pentamidine for Pneumocystis carinii pneumonia. Ann Intern Med 1987; 107:495-498 5. Bernard EM, Schmitt HJ, Lifton A, et al: Prevention of Pneumocystis carinii Pneumonia With Aerosol Pentamidine (Abstr). IV International Conference on AIDS, Stockholm, Sweden, June 1988 6. Girard PM, Landman R, Gaudebout C, et al: Prevention of Pneumocystis carinii pneumonia relapse by pentamidine aerosol in zidovudine-treated AIDS patients. Lancet 1989; 1:1348-1353 7. Montgomery AB, Debs RJ, Luce JM, et al: Selective delivery of pentamidine to the lungs by aerosol. Am Rev Respir Dis. 1988: 137:477-478

86 8. Anderson CD, Barrie HJ: Fatal pneumocystis pneumonia in an adult. Am J Clin Pathol 1960; 34:365-370 9. Livingstone CS: Pneumocystis pneumonia occurring in a family with agammaglobulinemia. Can Med Assoc J 1964; 90:1223-1225 10. Jarnum S, Rasmussen EF, Ohlsen AS, et al: Generalized Pneumocystis carinii infection with severe idiopathic hypoproteinemia. Ann Intern Med 1968; 68: 138-145 11. Barnett RN, Hull JG, Vortel V, et al: Pneumocystis carinii in lymph nodes and spleen. Arch Pathol 1969; 88:175-180 12. Awen CF, Baltzan MA: Systemic dissemination of Pneumocystis carinii pneumonia. Can Med Assoc J 1971; 104:809-812 13. Burke BA, Good RA: Pneumocystis carinii infection. Medicine (Baltimore) 1973; 52:23-51 14. LeGolvan DP, Heidelberger KP: Disseminated, granulomatous Pneumocystis carinii pneumonia. Arch Pathol 1973; 95:344-348 15. Rahimi SA: Disseminated Pneumocystis carinii in thymic alymphoplasia. Arch Pathol 1974; 97:162-165 16. Henderson DW, Humeniuk V, Meadows R, et al: Pneumocvstis carinii pneumonia with vascular and lymph nodal involvement. Pathology 1974; 6:235241 17. Price RA, Hughes WT: Histopathology of Pneumocvstis carinii infestation and infection in malignant disease in childhood. Hum Pathol 1974; 5:737-752 18. Rossi JF, Dubois A, Bengler C, et al: Pneumocystis carinii in bone marrow (Letter). Ann Intern Med 1985; 102:868 19. Carter TR, Cooper PH, Petri WA, et al: Pneumocystis carinii infection of the small intestine in a patient with acquired immune deficiency syndrome. Am J Clin Pathol 1988; 89:679-683 20. Unger PD, Rosenblum M, Krown SE: Disseminated Pneumocvstis carinii infection in a patient with acquired immunodeficiency syndrome. Hum Pathol 1988; 19:113-116 21. Macher AM, Bardenstein DS, Zimmerman LE, et al: Pneumocystis carinii choroiditis in a male homosexual with AIDS and disseminated pulmonary and extrapulmonary P carinii infection (Letter). N Engl J Med 1987; 316:1092 22. Grimes MM, LaPook JD, Bar MH, et al: Disseminated Pneumocystis carinii infection in a patient with acquired immunodeficiency syndrome. Hum Pathol 1987; 18:307-308 23. Coulman CU, Greene I, Archibald RWR: Cutaneous pneumocystosis. Ann Intern Med 1987; 106:396-398 24. Schinella RA, Breda SD, Hammerschlag PE: Otic infection due to Pneumocvstis carinii in an apparently healthy man with antibody to the human immunodeficiency virus. Ann Intern Med 1987; 106:399-400 25. Kwok S, O'Donnell JJ, Wood IS: Retinal cotton-wool spots in a patient with Pneumocystis carinii infection. N Engl J Med 1982; 307:184-185

ALERTS, NOTICES, AND CASE REPORTS 26. Pilon VA, Echols RM, Celo JS, et al: Disseminated Pneumocystis carinii infection in AIDS. N Engl J Med 1987; 316:1410-1411 27. Raviglione MC, Mariuz P, Sugar J, et al: Extrapulmonary Pneumocystis infection (Letter). Ann Intern Med 1989; 111:339 28. Richie TL, Yamaguchi E, Virani NA, et al: Extrapulmonary Pneumocystis infection (Letter). Ann Intern Med 1989; 111:339-340 29. Hardy WD, Northfelt DW, Drake TA: Fatal, disseminated pneumocystosis in a patient with acquired immunodeficiency syndrome receiving prophylactic aerosolized pentamidine. Am J Med 1989; 87:329-331 30. Sparling TG, Dong SR, Hegedus C, et al: Aerosolized pentamidine and disseminated infection with Pneumocystis carinii. Ann Intern Med 1989; 1 11:442 31. Poblete RB, Rodriguez K, Foust RT, et al: Pneumocystis carinii hepatitis in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 1989; 110:737-738 32. Piot D, Gathe J, del Junco G, et al: Splenic Pneumocystosis-Poster MBP377, In Abstracts, Vth International Conference on AIDS, Montreal, Quebec, 1989, p 284 33. Hagopian WA, Huseby JS: Pneumocystis hepatitis and choroiditis despite successful aerosolized pentamidine pulmonary prophylaxis. Chest 1989; 96:949-95 1 34. Davey RT Jr, Margolis D, Kleiner D, et al: Digital necrosis and disseminated Pneumocystis carinii infection after aerosolized pentamidine prophylaxis. Ann Intern Med 1989; 111:681-682 35. Afessa B, Green WR, Williams WA, et al: Pneumocystis carinii pneumonia complicated by lymphadenopathy and pneumothorax. Arch Intern Med 1988; 148:2651-2654 36. Hughes WT, McNobb PC, Makres TD, et al: Efficacy of trimethoprim and sulfamethoxazole in the prevention and treatment of Pneumocystis carinii pneumonitis. J Infect Dis 1973; 128:607-611 37. Hughes WT, Kuhn S, Chaudhary S, et al: Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1977; 297:1419-1426 38. Harris RE, McCallister JA, Allen SA, et al: Prevention of Pneumocystis carinii pneumonia: Use of continuous sulfamethoxazole-trimethoprim therapy. Am J Dis Child 1980; 134:35-38 39. Centers for Disease Control: Guidelines for prophylaxis against Pneumocystis carinii pneumonia for persons infected with human immunodeficiency virus. MMWR 1989; 38(suppl):1-9 40. Gordan FM, Simon GL, Wofsy CB, et al: Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1984; 100:495-499 41. Wharton JM, Coleman DZ, Wofsy CB, et al: Trimethoprim-sulfamethoxazole or pentamidine for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome-A prospective randomized trial. Ann Intern Med 1986; 105:37-44